Effects of dietary interventions on cardiovascular outcomes: a network meta-analysis

Abstract Context Next to a large body of epidemiological observational studies showing that the Mediterranean diet (MD) is an important lifestyle determinant of cardiovascular risk, there is less relevant evidence from well-conducted randomized controlled trials (RCTs) with hard cardiovascular outcomes. Objective The objective of the study was to identify the most effective dietary intervention for reducing cardiovascular morbidity and mortality. Data Sources A systematic approach following PRISMA network meta-analyses reporting guidelines was applied to a search of electronic databases (MEDLINE, Cochrane Central Register of Controlled Trials, and Embase) without language restrictions, supplemented by scanning through bibliographies of studies and meetings’ abstract material. Inclusion criteria were RCTs conducted in an adult population, investigating the effects of different type of diets or dietary patterns on all-cause mortality and cardiovascular outcomes of interest. Data Extraction Data extraction for each study was conducted by 2 independent reviewers. Data Analysis A frequentist network meta-analysis using a random-effects model was conducted. Death from any cardiovascular cause was defined as the primary outcome. A total of 17 trials incorporating 83 280 participants were included in the systematic review. Twelve articles (n = 80 550 participants) contributed to the network meta-analysis for the primary outcome. When compared with the control diet, only the MD showed a reduction in cardiovascular deaths (risk ratio = 0.59; 95% confidence interval, 0.42–0.82). Additionally, MD was the sole dietary strategy that decreased the risk of major cardiovascular events, myocardial infarction, angina, and all-cause mortality. Conclusions MD may play a protective role against cardiovascular disease and death for primary and also secondary prevention. Systematic Review Registration Center for Open Science, https://doi.org/10.17605/OSF.IO/5KX83


INTRODUCTION
Globally, cardiovascular disease (CVD) continues to be the leading cause of mortality and morbidity.High blood pressure measurements, triglyceride and total cholesterol concentrations, and body mass index are among the predisposing factors for CVD. 1 Dietary factors seem to have the cornerstone role for the prevention of CVD outcomes across Europe. 2 The Mediterranean diet (MD) is 1 of the most wellstudied dietary patterns.4][5] Next to a large body of epidemiological observational studies showing that the MD is an important lifestyle determinant of CVD risk, 3,6,7 there is less relevant evidence from well-conducted randomized controlled trials (RCTs) with hard cardiovascular outcomes.The Prevention of Cardiovascular Disease with a Mediterranean Diet (PREDIMED) study, a large RCT focused on the primary prevention of CVD among patients with a high cardiovascular risk, demonstrated that MD was associated with a lower incidence of major cardiovascular events. 8owever, a recent umbrella review showed that none of the included dietary interventions could reduce cardiovascular events and only the use of omega-3 fatty acids and folate supplementation might reduce some cardiovascular end points. 91][12] Therefore, in this network meta-analysis (NMA) of RCTs, we synthesized direct and indirect evidence across the literature to identify the most effective dietary intervention for CVD prevention.

MATERIALS AND METHODS
The Preferred Reporting Items for Systematic Reviews and meta-analyses extension statement for network meta-analyses (PRISMA-NMA) were followed in this systematic review and NMA. 13 A pre-specified protocol has been registered in the Open Science Framework (OSF) database (https://doi.org/10.17605/OSF.IO/ 5KX83).

Data sources and searches
The MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Embase databases were used for all searches from inception to May 31, 2022, with no language restrictions.A search strategy was created for PubMed and was accordingly modified for the other electronic databases (see Supplementary Material 1 in the Supporting Information online).Conference abstracts from major nutrition and metabolism conferences and references of relevant studies were screened.The PROSPERO database was searched to retrieve possible similar, ongoing systematic reviews to avoid duplication with this study. 14,15clusion and exclusion criteria RCTs were included that compared either 2 specific dietary interventions or a dietary intervention with a control diet, regardless of the study design (parallel or crossover) and that reported at least 1 event of the following: all-cause mortality, cardiovascular-related death, myocardial infarction, stroke, angina, heart failure, atrial fibrillation (PICOS criteria are reported at Table 1).Cardiovascular death was set as the primary endpoint.The initial search included a plethora of different dietary interventions, but few of these were used among eligible studies: Mediterranean diet, 8,[16][17][18] lowfat diet, 19,20 low-protein diet, 21 low-salt diet, 22,23 normal or usual diet. 24onrandomized controlled trials, observational studies, and studies performed with children and adolescents were excluded from this review.

Study selection
Retrieved articles were imported into a reference manager (EndNote X7).After duplicate removal, 4 pairs of 2 independent reviewers (A.Konstantelos, A. Karligkiotis, A.S., E.K., E.M., G.K., L.C., and M.C.) first assessed titles and abstracts and then evaluated full texts for eligible studies.Any disagreements were adjudicated by an additional reviewer (I.D.).

Data extraction
Data extraction for each study was conducted by 2 pairs of 2 independent reviewers (I.D., I.F., S.Z., and S.S.), and discrepancies were settled through consensus.A predesigned data collection form was used to extract data on study participants' baseline characteristics, as well as their outcomes.Crossover data were extracted solely from the first period. 25

Quality assessment
The revised Cochrane risk-of-bias tool (RoB 2.0) was used by 2 reviewers (S.S. and S.Z.) to independently assess the quality of the included studies. 26Any discrepancies were resolved by a third reviewer (I.D.).

Certainty of the evidence
The Confidence in Network Meta-Analysis approach was applied to assess the certainty of the findings. 27

Data synthesis and analysis
To combine direct and indirect evidence across trials, a frequentist NMA with a random-effects model was used.Risk ratios (RRs) with the appropriate 95% confidence intervals (CIs) were used to summarize the evidence.Global approaches, such as a design-bytreatment interaction model, 28 and local ones, such as analyzing consistency across direct and indirect comparisons with the node-splitting method, were used to measure consistency.The P value was used to categorize dietary interventions in a hierarchical order. 29ublication bias was evaluated using the comparisonadjusted funnel plot. 30The analyses were conducted using the netmeta package in R, version 3.6.3(the R Project for Statistical Computing).

Overview of studies
After the removal of duplicates, 107 305 records were evaluated on the basis of their title and abstract (Figure 1).2][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] The summaries of the included studies are listed in Table 1.The risk of bias was judged as low in 6 studies, with some concerns in 4 studies, and was judged high in 7 studies (see Supplementary Figure S1 in the Supporting Information online).Supplementary Table S1 in the Supporting Information online provides the dietary details in each interventional arm.

Network meta-analysis
Cardiovascular death.[44][45][46]48 Figure 2 visualizes the NMA graph.Only the MD decreased the risk of cardiovascular death when compared with the control diet (RR ¼ 0.59; 95%CI, 0.42-0.82)(Figure 3).There was a difference between the low-fat diet and MD (RR ¼ 1.46; 95%CI, 1.07-1.99),but not with MD and a reduced-salt diet (RR ¼ 0.65; 95%CI, 0.31-1.38)(Table 2).MD ranked best (P ¼ 0.9532), followed by the low-fat diet (P ¼ 0.4565), reduced-salt diet (P ¼ 0.3997), and the control diet (P ¼ 0.1905).No disagreement was detected between direct and indirect evidence with the node-splitting method.Evidence of publication bias was absent in the network (Egger's test, P ¼ 0.7812).Supplementary Material 2 in the Supporting Information online provides further information on consistency, the funnel plot, and the influence of individual studies on the network of the primary outcome.
]43,45,48 Compared with the control diet, no difference was observed between the dietary interventions (Figure 3).A low-fat diet was associated with an increased risk for stroke, compared with the MD (RR ¼ 1.34; 95%CI, 1.05-1.70)(see Table S5 in the Supporting Information online).In the subgroup analysis of studies including exclusively patients with established CVD (n ¼ 6 studies; n ¼ 5757 patients), 35,38- 40,43,48 the same results were observed.According to Egger's test, there was publication bias (P ¼ 0.0118) regarding to this outcome.
3,45 Compared with the control diet, only the MD reduced the mortality risk (RR ¼ 0.64; 95%CI, 0.49-0.84)(Figure 3).Furthermore, a low-fat diet was associated with an increased risk for stroke compared with the MD (RR ¼ 1.53; 95%CI, 1.18-1.97)(see Table S6 in the Supporting Information online).MD ranked as the best intervention in terms of effect on major cardiovascular events (P ¼ 0.9851), whereas the reduced-salt diet was the worst dietary plan (P ¼ 0.2948).There was a difference between the MD and low-fat diet (RR ¼ 1.53; 95%CI, 1.18-1.97),but not between the MD and the reduced-salt diet (RR ¼ 0.61; 95%CI, 0.35-1.07).Six studies (n ¼ 7659 patients) contributed to the NMA for the angina outcome (see Supplementary Material 7 in the Supporting Information online). 35,38,39,41,43,45Compared with the control diet, only the MD reduced the mortality risk (RR ¼ 0.36; 95%CI, 0.16-0.84)(Figure 3).There was no difference between the low-fat diet and the MD (RR ¼ 1.83; 95%CI, 0.72-4.65)(see Table S7 in the Supporting Information online).
0 There was no differences among the MD, low-fat diet, and control diet (see Table S8 in the Supporting Information online).

Grading of evidence
Moderate confidence evidence demonstrated that only the MD managed to decrease the cardiovascular mortality risk (see Supplementary Table S9 in the Supporting Information online) when compared with control diets.

DISCUSSION
In this study, the comparative efficacy of dietary interventions for CVD prevention was assessed by an NMA.Moderate confidence evidence suggests that, compared with the control diet, only the MD decreased the cardiovascular mortality risk.In addition, the MD was the only effective intervention for decreasing all-cause mortality, myocardial infarction, angina, and major cardiovascular events.
The MD contains higher quantities of fruit, vegetables, nuts, fish, and olive oil. 17These quantities have beneficial effects on cardiometabolic markers, endothelial function, and inflammation, decreasing the incidence of cardiovascular outcomes. 49A recent study showed that greater amounts of olive oil consumption   The upper triangle contains the pooled effect sizes expressed as risk ratios and their 95% confidence intervals of the direct comparisons available in our network.The lower triangle of the matrix contains the estimated effect sizes expressed as risk ratios and their 95% confidence intervals for each comparison.Significant results are in bold.
reduce total CVD and deaths from cancer. 502][53] Furthermore, the latest European guidelines recommend an MD or similar diet to lower the risk of CVD. 12 Nonetheless, it should be highlighted that this evidence is not supported by well-conducted, head-tohead comparisons (with few exceptions) 8,35,37,48 among dietary interventions (trials or NMAs).
According to the NMA findings, the MD is the only effective intervention for the primary and secondary prevention of CVD.Results of a previous RCT with 423 patients with myocardial infarction indicated that the MD had a positive effect on myocardial infarction 4 years after its first incidence. 39Moreover, Estruch et al 8 provided data on patients with a poor cardiac profile.The repercussion of significant cardiovascular outcomes in this study was lower among those assigned to the intervention arms in comparison with those assigned to a reduced-fat diet.Indeed, evidence from cohort studies has shown that greater amounts of olive oil intake were also correlated with beneficial outcomes. 50The retracted and republished PREDIMED trial results showed that there was no alteration in the studied outcomes, even after the reanalysis of the data.It was concluded that participants assigned to the MD arms had almost 30% lower incidence of CVD in contrast to individuals who received a control diet.Indeed, this NMA confirmed these results compared with lowfat, reduced-salt, and usual diets.
None of the included RCTs in this review evaluated the cardiovascular benefits of plant-based diets.This intervention might have a key role in CVD prevention.In previous cohorts, lower levels of blood pressure and low-density lipoprotein cholesterol, and reduced incidence of type 2 diabetes mellitus were associated with this diet. 54,55A recent meta-analysis of observational studies showed that plant-based diets were associated with a lower risk of CVD. 56Thus, European guidelines have included this intervention as a food pattern for people at high cardiovascular risk. 12lthough this NMA provides evidence in the field, the findings must be interpreted with caution.Among the included studies, some were published before the introduction of the Consolidated Standards of Reporting Trials statement; hence, they may lack rigor of methodology.Although the MD remains the best option in the subgroup analysis of studies including exclusively patients with established CVD, it is unknown whether the benefits of diets are evident in other specific populations, such as elderly patients or patients with diabetes mellitus.An additional limitation identified in the studies included in our NMA was that participants following the MD diet achieved greater weight loss than did population groups assigned to other dietary interventions.Hence, the overall reduction of CVD risk may be attributed to changes in body weight and not to dietary interventions per se.Some of the included trials were published before 2000 and had methodological issues.

CONCLUSION
The MD may have a protective role against cardiovascular death and for primary and secondary prevention of CVD.

Figure 1
Figure 1 PRISMA flowchart of the study selection process.

Figure 2
Figure 2 The network graphs of interventions for the outcomes.

Figure 3
Figure3Forest plot of the network estimates of the potent dietary intervention against control diet for the outcomes.

Table 1
Characteristics (PICOS [population, intervention, comparison, outcomes, study design] criteria) of randomized clinical trials a included in this systematic review, in chronological order a All studies are randomized controlled trials according to inclusion criteria.Abbreviations: CAD, coronary artery disease; CV, cardiovascular; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MACE, myocardial infarction, stroke, or cardiovascular mortality; MI, myocardial infarction.

Table 2
League table showing the results of the network meta-analyses comparing the effects of interventions for the primary outcome a